ACE inhibitors are compounds which inhibit the conversion of angiotensine I into the active angiotensine II as well as the breakdown of the active vasodilator bradykinin. Both of these mechanisms lead to vasodilation. Such compounds have been described in, for example, EP 158927, EP 317878, U.S. Pat. No. 4,743,450, and U.S. Pat. No. 4,857,520. Ramipril (disclosed in EP 079022) is a long-acting ACE inhibitor. Its active metabolite is the free acid ramiprilat, which is obtained in vivo upon administration of ramipril. In hypertensive patients administration of ramipril is known to cause a reduction in peripheral arterial resistance and thus a reduction of the blood pressure without a compensatory rise in heart rate. It is being used in the treatment of hypertension and congestive heart failure. Furthermore, ramipril has been shown to reduce mortality in patients with clinical signs of congestive heart failure after surviving an acute myocardial infarction. Ramipril has been suggested to have an added advantage over many other ACE inhibitors due to its pronounced inhibition of ACE in tissues resulting in organ protective effects in e.g. the heart, lung, and kidney.
Ramipril substance is sensitive to high temperature, moisture or compression and therefore, upon formulation into pharmaceutical preparations needs special attention in order to retain its stability (U.S. Pat. No. 5,151,433).
Calcium antagonists are compounds which influence the inflow of calcium ions into cells, in particular into the cells of smooth muscles. Such compounds of the dihydropyridine type have been described in, for example, GB 1358951 (nitrendipine), U.S. Pat. No. 3,644,627 (nifedipine), EP 007293 (felodipine), and GB 2164336 (lacidipine).
The most common adverse events which are observed in clinical use of the ACE inhibitor and the calcium antagonists of this invention are headache, coughing, peripheral oedema, flush, dizziness, fatigue and nausea.
Some dihydropyridines, for example nifedipine and felodipine are decomposed when exposed to light, and therefore, upon handling and formulation into pharmaceutical preparations need special attention in order to retain their stability.
Combinations of ACE inhibitors and calcium antagonists of dihydropyridine type in the treatment of hypertension have been described in, for example EP 488059, EP 180785 and EP 265685.
Bainbridge, A.D. et al. (Br. J. Clin. Pharmac. 1993, 36: 323-330) have studied the use of the angiotensin converting enzyme inhibitor ramipril and an extended release formulation of the dihydropyridine calcium channel antagonist felodipine given in free combination as separate dosage forms.
In U.S. Pat. No. 4,703,038 solid combinations for oral administration of certain ACE inhibitors and certain dihydropyridine compounds including i.a. nitrendipine and felodipine are described. This document also describes a method of treating hypertension in man using such combinations. U.S. Pat. No. 4,703,038 does not, however, disclose ramipril as an ACE inhibitor. Neither does it describe the use of extended release formulations of dihydropyridines.
In U.S. Pat. No. 5,236,933 the use of combinations of certain ACE inhibitors including i.a. ramipril, and certain calcium antagonists, i.a. felodipine have been described in the prevention and/or treatment of proteinuria.